1. Field of the Invention
This invention relates to 1,2-dihydroquinoline derivatives and methods for their use in treating HIV infections. These compounds are useful for treating retrovirus-associated cancer, and modulating reverse transcriptase, RNase, HIV polymerase.
2. Related Background Art
The retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system and degeneration of the central and peripheral nervous system (acquired immune deficiency syndrome; AIDS). A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds such as nucleoside and non-nucleoside reverse transcriptase inhibitors, which interfere with the function of this enzyme, have shown utility in the treatment of conditions including AIDS.
Presently, there are four categories of drugs used to treat HIV infection, which include nucleoside analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Reverse transcriptase inhibitors, including the nucleoside and non-nucleoside categories, interfere with HIV reverse transcriptase, which, as noted above, is required for viral replication. Protease inhibitors interfere with the enzyme protease, which plays a major role in viral infection. Forms of anti-HIV therapy include giving only one reverse transcriptase inhibitor at a time (monotherapy), a combination of two or more reverse transcriptase inhibitors (combination therapy), and a combination of reverse transcriptase inhibitors and protease inhibitors (combination therapy with protease inhibitors). Nucleoside analogues include AZT (zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine, Epivir), d4T (stavudine, Zerit), abacavir (Ziagen) and ddC (zalcitabine, Hivid). AZT and 3TC are also available in a single combined pill called Combivir and AZT, 3TC and abacavir are available in a single combined pill called Trizivir. Tenofovir (Viread), a nucleotide analogue, is the only nucleotide analogue currently available for prescription and is only licensed to give people on their second or later treatment combination, although it may be given to people in their first-line treatment. Nucleotide analogues are very similar to nucleoside analogues. The only difference is that nucleotide analogues, unlike nucleoside analogues, are chemically preactivated and thus require less processing in the body for them to become active. Non-nucleoside reverse transcriptase inhibitors include Sustiva, nevirapine (Viramune), and delavirdine (Rescriptor).
Many of the treatments which inhibit reverse transcriptase activity that are currently available, particularly the nucleoside analogues, are associated with serious side effects and require long term treatment to be effective. In addition, the virus is able to mutate in response to the drugs and becomes resistant to them. Therefore, there is a constant need to provide new and better treatments for HIV and AIDS and particularly new drugs that inhibit HIV reverse transcriptase.
Derivatives of 1,2-dihydroquinoline are known to possess activity which make them useful as herbicides and therapeutic agents.
1,2-Dihydroquinoline derivatives are disclosed in European Patent Application No. 0 579 469 for use as herbicides with selectivity between crops and weeds.
The following U.S. patents disclose 1,2-dihydroquinoline derivatives which have activity that may be useful in the treatment of various diseases. U.S. Pat. No. 4,968,680 discloses compounds that are potent diuretic agents that may be useful in the treatment of hypertension, edema, and removing ascites. Potassium channel activating compounds for use as antiischemic agents were described in U.S. Pat. No. 5,514,690. In U.S. Pat. No. 6,511,966, 1,2-dihydroquinoline compounds that are mitochondria protecting agents were disclosed. These compounds are useful for treating diseases in which mitochondrial dysfunction leads to tissue degeneration, such as Alzheimer's disease, diabetes mellitus and Parkinson's disease. Compounds capable of increasing HDL-C concentrations for the treatment of dyslipoproteinanians and coronary heart disease were disclosed in U.S. Pat. No. 5,939,435. 1,2-Dihydroquinoline compounds described in U.S. Pat. No. 6,093,821 are modulators of steroid receptors.
The International Publication No. WO 92/16508 discloses 1,2-dihydroquinoline compounds that are useful for the treatment of AIDs and related complexes, but these compounds differ in structure from those of the present invention.
U.S. Pat. No. 6,388,081 discloses combination libraries containing two or more 1,2-dihydroquinoline derivatives and methods of generating such libraries.